Synergists are used to improve potency and reduce costs associated with expensive active principles, such as those used in pesticides and pharmaceuticals.
Dillapiol, a naturally occurring monoligan found in many plant families, has been demonstrated to act as a synergist. It has shown promise in the area of insecticidal activity, where co-administration of dillapiol with alpha-terthienyl, a phototoxic larvicide, increased toxicity in mosquito larvae by a synergism factor of 1.9 (Belzile et al, 2000, Pest. Biochem. Physiol., 66:33-40). Synergism has also been demonstrated in vivo, where co-administration of dillapiol with the plant-derived antimalarial compound genudin increased parasitemia clearance in mice by 29% (Omar et al., 2003 Ann. Appl. Biol., 143(2):135-141). A mechanism for dillapiol's observed synergism is suggested by the observation that it inhibits the human cytochrome P450 3A4 (CYP3A4) enzyme, a key metabolic enzyme (Budzinski et al., 2000, Phytomedicine, 7(4):273-282).
The cytochrome P450s (CYPs) are an important family of enzymes responsible for many Phase I metabolic biotransformations. CYP3A4 is the most prominent member of the CYP family responsible for metabolism of more than 60% of all xenobiotics, such as pesticides and pharmaceuticals. Recently, there has been interest in inhibiting CYP3A4 to increase drug concentration and/or activity of active principles in the body. The effect of CYP inhibition is pharmaco-enhancement, where CYP3A4 inhibitors are co-administered, at sub-therapeutic levels, with a second active principle thereby synergistically increasing the activity of the second active principle. In this way a lower dose of the second active principle can be used to elicit the same therapeutic or inhibitory effect. This approach has been used with success in anti-HIV treatment where the CYP3A4 inhibitor ritonavir is paired with protease inhibitors in therapeutic drug “cocktails”. Recently this enhancement has been extended with the synthesis of ritonavir derivatives that are more potent inhibitors and pharmaco-enhancers (Flentge et al., 2009, Bioorg. Med. Chem. Lett. 19(18):5444-5448).
Dillapiol has a long history of human food use since it constitutes about 30% of Indian Dill Oil, and is therefore generally recognized as safe (GRAS). Syntheses of dillapiol and several derivatives have also been reported (Majeurus et al., 2000, Can. J. Chem. 78:1345-1355; Belzile et al, 2000, Pest. Biochem. Physiol., 66:33-40). However, none of these derivatives have been investigated as synergists for pyrethrins or other insecticides, or as potential pharmaco-enhancers.
Sesamol is a natural organic compound which is a component of sesame oil. Sesamol has been found to be an antioxidant that may prevent the spoilage of oils, and may protect the body from damage from free radicals (Ohsawa, Toshiko. “Sesamol and sesaminol as antioxidants” New Food Industry (1991), 33(6), 1-5). It also may prevent the spoilage of oils by acting as an antifungal (Wynn, James P.; Kendrick, Andrew; Ratledge, Colin. “Sesamol as an inhibitor of growth and lipid metabolism in Mucor circinelloides via its action on malic enzyme.” Lipids (1997), 32(6), 605-610). Sesame oil is used in Ayur-Vedic Medicine.
Accordingly, there is considerable potential for dillapiol, derivatives derived from it and related monolignans as synergists in both the pesticide and pharmaceutical fields.